{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T04:24:36Z","timestamp":1785558276022,"version":"3.56.0"},"reference-count":37,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Indomethacin is commonly used in the Neonatal Intensive Care Unit (NICU) for intraventricular hemorrhage (IVH) prophylaxis and patent ductus arteriosus (PDA) treatment, yet unpredictable clinical efficacy and toxicity occur with standard weight\u2010based dosing. Model\u2010informed precision dosing (MIPD) produces individualized doses to overcome deficiencies of standard dosing. To identify an indomethacin therapeutic index for MIPD to target, exposure\u2013response relationships (ERRs) were determined. Indomethacin pharmacokinetic and demographic data collected from preterm infants treated at two US NICUs were leveraged. The following ERRs were assessed: (1) AUC<jats:sub>0\u2013\u221e<\/jats:sub> and IVH prevention efficacy (non\u2010severe vs. severe), (2) AUC<jats:sub>course<\/jats:sub> (course start to end+12\u2009h) and PDA treatment efficacy (success vs. failure), and (3) <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> and renal toxicity (urine output nadir within 12\u2009h after dose [UOP<jats:sub>nadir<\/jats:sub>]). A previously developed indomethacin population pharmacokinetic model was used to predict exposure estimates. For the ERR analyses, fixed\u2010effect or mixed\u2010effect regression models (linear or logistic) were used. Data from 83 neonates were available for analysis. The regression analyses supported a lack of an ERR for IVH prevention and PDA treatment efficacy, with only gestational age as the significant predictor of IVH severity. <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> was a significant modulator of natural log UOP<jats:sub>nadir<\/jats:sub> and was used to simulate UOP<jats:sub>nadir<\/jats:sub> &lt;\u20090.5 and &lt;\u20091\u2009mL\/kg\/h for renal toxicity. On average, these levels were reached with <jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub> values of 22 and 14\u2009\u03bcg\/mL, respectively. Although an ERR exists for indomethacin renal toxicity, the lack of ERR for indomethacin efficacy may indicate that current dosing does not give exposures sufficiently high to observe an ERR.<\/jats:p>","DOI":"10.1111\/cts.70251","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T09:09:46Z","timestamp":1747818586000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Relationship of Indomethacin Exposure With Efficacy and Renal Toxicity Outcomes for Preterm Infants in the Neonatal Intensive Care Unit"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2334-6376","authenticated-orcid":false,"given":"Cindy H. T.","family":"Yeung","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology &amp; Toxicology The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"College of Pharmacy Dalhousie University  Halifax Nova Scotia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7920-772X","authenticated-orcid":false,"given":"Deanna C.","family":"Sekulich","sequence":"additional","affiliation":[{"name":"Mildred T. 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Stahlman Division of Neonatology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil","family":"Maharaj","sequence":"additional","affiliation":[{"name":"Faculty of Pharmaceutical Sciences The University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.puhe.2014.03.010"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-3848(11)70032-9"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2015-0944"},{"key":"e_1_2_9_5_1","first-page":"109","article-title":"The Frequency of Intraventricular Hemorrhage and Its Risk Factors in Premature Neonates in a Hospital's NICU","volume":"15","author":"Basiri B.","year":"2021","journal-title":"Iran Journal of Child Neurology"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2020.101120"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41372-020-00772-2"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2021.648584"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2021.08.075"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197609022951003"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM197609022951004"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200106283442602"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/siny.2000.0036"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2015-309112"},{"key":"e_1_2_9_15_1","article-title":"Prophylactic Cyclo\u2010Oxygenase Inhibitor Drugs for the Prevention of Morbidity and Mortality in Preterm Infants: A Network Meta\u2010Analysis","volume":"4","author":"Mitra S.","year":"2022","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2023-325445"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41372-019-0509-4"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41372-020-00814-9"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-013-0031-7"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2049"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.659"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1315"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12490"},{"issue":"1345969","key":"e_1_2_9_24_1","article-title":"Pharmacokinetic and Pharmacodynamic Principles: Unique Considerations for Optimal Design of Neonatal Clinical Trials","volume":"11","author":"Yeung C. 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